Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 1 de 1
Filtrar
Mais filtros

Base de dados
Ano de publicação
Tipo de documento
País de afiliação
Intervalo de ano de publicação
1.
Bioorg Med Chem ; 27(17): 3788-3796, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31320211

RESUMO

Novel analogs of the allosteric, biased PAR1 ligand ML161 (parmodulin 2, PM2) were prepared in order to identify potential anti-thrombotic and anti-inflammatory compounds of the parmodulin class with improved properties. Investigations of structure-activity relationships of the western portion of the 1,3-diaminobenzene scaffold were performed using an intracellular calcium mobilization assay with endothelial cells, and several heterocycles were identified that inhibited PAR1 at sub-micromolar concentrations. The oxazole NRD-21 was profiled in additional detail, and it was confirmed to act as a selective, reversible, negative allosteric modulator of PAR1. In addition to inhibiting human platelet aggregation, it showed superior anti-inflammatory activity to ML161 in a qPCR assay measuring the expression of tissue factor in response to the cytokine TNF-alpha in endothelial cells. Additionally, NRD-21 is much more plasma stable than ML161, and is a promising lead compound for the parmodulin class for anti-thrombotic and anti-inflammatory indications.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Oxazóis/farmacologia , Receptor PAR-1/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Regulação Alostérica/efeitos dos fármacos , Anti-Inflamatórios não Esteroides/química , Relação Dose-Resposta a Droga , Estabilidade de Medicamentos , Humanos , Ligantes , Estrutura Molecular , Oxazóis/síntese química , Oxazóis/química , Agregação Plaquetária/efeitos dos fármacos , Receptor PAR-1/metabolismo , Relação Estrutura-Atividade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA